Summary/Abstract: This application addresses Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101*: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Heart failure (HF) remains a leading cause of morbidity and mortality in Western countries, affecting more than 5 million people in the United States alone. HF patients are at risk of dying primarily of sudden cardiac death (SCD) or progressive pump failure. The overall goals of this proposal are to develop transcriptomic (mRNA and miR) biomarkers to aid identification of patients that are truly at high risk of (a) SCD and (b) worsening HF among a group of patients that is considered to be at a high risk for SCD and HF based on their low LV ejection fraction. The prognosis of patients diagnosed with HF is poor and current methods used to predict the clinical course and assess risk of SCD or overall mortality are limited. The frontline management of lethal arrhythmias and SCD in patients with a left ventricular ejection fraction <35% is the use of the implantable cardioverter defibrillator (ICD). However, this strategy reflects major limitations in the current understanding of SCD, as existing risk-stratification algorithms (based largely on ejection fraction) are neither sensitive nor specific;they require implantation of more than 10 ICDs for every device that saves a life. The high cost and procedural hazards of device implantation limit the use of prophylactic ICDs to high-risk populations, while the overwhelming majority of SCDs occur in lower- risk patients. Likewise, despite comparably low ejection fractions, some HF patients develop frequent episodes of cardiac decompensation that require costly hospitalizations, while others remain clinically stable during follow-up. Identifying heart failure patients at high-risk of cardiac decompensation is highly desirable, as disease and complex case management programs have demonstrated positive effects on mortality, quality of life, and length of hospitalization in these patients. There is an extensive body of literature to suggest that inflammatory processes contribute to both the pathophysiology of HF and arrhythmogenesis associated with SCD. As peripheral blood mononuclear cells (PBMC) have crucial roles in immunity and inflammation, the objectives of this proposal are to develop a transcriptomic biomarker based on gene expression profiling of PBMC in order to identify patients at high risk for SCD and worsening HF. This study will leverage the strengths of a well-established ongoing prospective cohort study based at the Johns Hopkins University: The PRospective Observational Study of ICD (PROSE-ICD) is a cohort study of 1200 patients with ischemic and non-ischemic cardiomyopathy (ejection fraction <35%) undergoing ICD implantation for primary prevention of SCD. For all PROSE-ICD patients, blood samples and extensive clinical and laboratory information are available. Enrollment of patients in the PROSE-ICD study is ongoing, thus allowing for prospective validation of genomic classifiers and novel differentially expressed transcripts. The unique strengths of this proposal are as follows: 1. Extensively phenotyped HF population with regular follow-up (every 6 months);long-term follow- up data are available (up to 5 years) 2. Blood samples are immediately available for analysis 3. Rigorous study design and standardization includes an FDA-approved system for whole blood collection and RNA stabilization (PAXgeneTM) 4. MIAME-compliant data analysis 5. Serial blood samples permit longitudinal analysis to test stability of genomic classifiers over time 6. Initial blood molecular signatures will be validated in independent cohorts of HF patients, as enrollment into the PROSE-ICD study is ongoing Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly, Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create or retain three jobs. PUBLIC HEALTH RELEVANCE: More than 5 million people in the United States alone have advanced heart disease with an increased risk of dying suddenly. The objectives of this proposal are two-fold: to enhance understanding of the biological mechanisms that predispose to sudden death and progressive heart failure and to develop a practical gene expression biomarker panel to identify patients with implanted defibrillators at greatest risk of sudden death and rehospitalizations for heart failure.